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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 劉宏輝 | zh_TW |
| dc.contributor.advisor | Horng-Huei Liou | en |
| dc.contributor.author | 陳恩莉 | zh_TW |
| dc.contributor.author | En-Li Chen | en |
| dc.date.accessioned | 2021-07-10T22:04:14Z | - |
| dc.date.available | 2024-02-28 | - |
| dc.date.copyright | 2019-03-11 | - |
| dc.date.issued | 2018 | - |
| dc.date.submitted | 2002-01-01 | - |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/77483 | - |
| dc.description.abstract | Dravet症候群是一種難治性癲癇，為嚴重的嬰幼兒肌陣攣性癲癇，具有延遲的精神和運動發育、自閉症與認知行為障礙等異常。癲癇發作通常伴隨著腦部發炎的症狀與微膠細胞的活化，而微膠細胞為中樞神經系統中的免疫細胞，不論是在發育中或是成熟的中樞神經系統，微膠細胞都會與神經有許多的連結與調控作用。過去的研究顯示微膠細胞會表達Scn1a基因編碼的第I型電壓門控鈉通道（Nav1.1）。而在Dravet症候群中，大多數病患都是屬於Scn1a基因突變，但Scn1a基因在微膠細胞中的作用仍是未知的。因此我們使用Scn1aE1099X基因轉殖小鼠建構了Dravet症候群的動物模型，在體外培養微膠細胞的方式探討Scn1a基因在微膠細胞上的角色。我們的結果首先發現在Nav1.1缺乏下，微膠細胞的存活率會顯著降低。在形態上則發現在靜態時，Nav1.1缺陷下的微膠細胞會呈現微活化的中間態形態，而不是正常的休息態分支結構。而在促炎細胞因子的表達上，發現在Scn1a的缺陷中，TNF-α、IL-1β和IL-6的mRNA表達均顯著的增加。同樣地，在Scn1a缺陷中，TNF-α和IL-6在細胞內和釋放的細胞外蛋白表現也都顯著增加。然而，抗炎性細胞因子TGF-β和IL-10以及指標基因Arg1的mRNA表達，在Scn1a缺陷中均顯著的降低。此外，我們也發現在Nav1.1缺陷微膠細胞的吞噬能力會減弱。另一方面，在LPS的刺激活化下，Nav1.1缺陷中微膠細胞的形態卻仍呈現微發炎活化的形態，而不是正常的變形蟲活化結構。此外，在LPS的刺激活化下，促炎細胞因子TNF-α、IL-1β和IL-6的mRNA表達在Scn1a缺陷中均顯著的減少。而在LPS刺激活化下的TNF-α和IL-6蛋白表現，以及在IL-4刺激活化下的抗炎細胞因子TGF-β和IL-10的mRNA表達與標誌物Arg1也都顯著的減少。這些結果顯示Scn1a突變體在靜態時會使微膠細胞傾向於更活化發炎的狀態，然而在給予刺激後卻呈現整體功能異常降低的現象，這些現象便可能造成Dravet症候群中異常的病理態，並且可能為癲癇發作的原因之一。 | zh_TW |
| dc.description.abstract | Dravet syndrome is a refractory seizure characterized by severe infant-onset myoclonic epilepsy, delayed psychomotor development and autism-spectrum behaviors. Patients with seizure attacks often follow by brain inflammation, leading to the activation of microglia cell. Microglia, CNS immune cell, have many communication and regulation with neuron in developing and adult CNS, and were observed to express the type I voltage-gated sodium channel (Nav1.1), which is encoded by the Scn1a gene. Loss-of-function mutation in Scn1a gene is the predominant molecular cause in most Dravet syndrome patients. However, the role of Scn1a gene in Microglia is unknown. Here, we constructed an animal model of Dravet syndrome with Scn1aE1099X knock-in (KI) allele transgenic mice, which exhibited epileptic discharges. Our results first show that Nav1.1 deficiency reduced the cell viability of microglia. At quiescence, the morphology of microglia under Nav1.1 deficiency showed an intermediate morphology, instead of normal branched structure, which showed a smaller cell size. The mRNA expression of pro-inflammatory cytokines, TNF-α, IL-1β and IL-6, were upregulated in Scn1a deficiency. Likewise, the intracellular and released extracellular protein level of TNF-α and IL-6 were upregulated in Scn1a deficiency. However, the mRNA expression of anti-inflammatory cytokines, TGF-β and IL-10, and the marker, Arg1, were downregulated in Scn1a deficiency. Furthermore, phagocytic function of microglia was reduced by deficit Nav1.1. On the other hand, the morphology of microglia under Nav1.1 deficiency still showed an intermediate morphology, instead of normal amoeboid activated structure which still showed a smaller cell size during LPS activation. Also, the mRNA expression of pro-inflammatory cytokines, TNF-α, IL-1β and IL-6, were downregulated in Scn1a deficiency during LPS activation. The protein level of TNF-α and IL-6 during LPS activation, and the mRNA expression of anti-inflammatory cytokines, TGF-β and IL-10, and the marker, Arg1 during IL-4 activation, were also all decreased. These results suggested that the Scn1a mutant drove microglia to a more inflamed state at quiescence, and attenuates the overall function of microglia after stimulation which led to an irregular pathology in Dravet syndrome and may be a cause of seizures. | en |
| dc.description.provenance | Made available in DSpace on 2021-07-10T22:04:14Z (GMT). No. of bitstreams: 1 ntu-107-R05443014-1.pdf: 6772697 bytes, checksum: d974f9d957e8358ad9d987af52ea4d3d (MD5) Previous issue date: 2018 | en |
| dc.description.tableofcontents | 摘要 III
Abstract V 圖目錄 VII 縮寫表 VIII 第一章 緒論（Introduction） 1 第一節 Dravet症候群（Dravet syndrome, DS） 1 第二節 電壓依賴型鈉離子通道（Voltage-gated sodium channel） 2 第三節 Dravet症候群之動物模型 4 第四節 微膠細胞（Microglia）在中樞神經系統（CNS）的角色 5 第五節 微膠細胞與癲癇疾病（Epilepsy）之關係 6 第六節 微膠細胞與電壓依賴型鈉離子通道 8 第七節 研究動機與目的 10 第二章 實驗材料與方法（Materials and Methods） 11 第一節 實驗動物 11 第二節 微膠細胞培養 11 第三節 細胞存活率分析（Cell viability assay） 12 第四節 微膠細胞的活化 13 第五節 免疫細胞螢光染色法（Immunocytochemistry） 13 第六節 即時聚合酶鏈鎖反應（Quantitative real time polymerase chain reaction, qPCR） 14 第七節 吞噬能力分析（Phagocytosis ability analysis） 14 第八節 酵素結合免疫吸附分析法（Enzyme-linked immunosorbent assay, ELISA） 15 第九節 微膠細胞型態分析（Analysis of microglia morphology） 15 第十節 統計分析 16 第三章 結果（Result） 17 第一節 Nav1.1表達在微膠細胞 17 第二節 Nav1.1缺陷改變靜態微膠細胞的存活率與型態特性 18 第三節 Scn1a缺陷改變靜態微膠細胞的發炎與抗發炎活化特性 19 第四節 Nav1.1缺陷影響微膠細胞的吞噬能力 21 第五節 Nav1.1缺陷影響受刺激微膠細胞的形態變化 21 第六節 Scn1a缺陷影響受刺激微膠細胞的發炎與抗發炎活化特性 23 第四章 討論（Discussion） 26 第一節 總述 26 第二節 鈉離子通道調控微膠細胞的生長 26 第三節 鈉離子通道參與在微膠細胞的發炎活化中 27 第四節 鈉離子通道參與在微膠細胞的抗發炎活化中 31 第五節 鈉離子通道影響微膠細胞的吞噬作用 32 第六節 未來展望 33 第五章 圖表（Figure） 35 參考文獻（Reference） 60 表一 免疫細胞螢光染色（Immunocytochemistry）使用之抗體 69 表二 即時聚合酶鏈鎖反應（qPCR）使用之primer 69 | - |
| dc.language.iso | zh_TW | - |
| dc.subject | 微膠細胞 | zh_TW |
| dc.subject | 促炎性活化態 | zh_TW |
| dc.subject | 抗炎性活化態 | zh_TW |
| dc.subject | 吞噬作用 | zh_TW |
| dc.subject | Scn1a | zh_TW |
| dc.subject | Nav1.1 | zh_TW |
| dc.subject | Dravet症候群 | zh_TW |
| dc.subject | Microglia | en |
| dc.subject | Dravet syndrome | en |
| dc.subject | Nav1.1 | en |
| dc.subject | Scn1a | en |
| dc.subject | phagocytosis | en |
| dc.subject | anti-inflammation | en |
| dc.subject | pro-inflammation | en |
| dc.title | Scn1a基因缺陷影響微膠細胞的功能與活化 | zh_TW |
| dc.title | The effect of Scn1a mutation on microglia function and activation | en |
| dc.type | Thesis | - |
| dc.date.schoolyear | 106-2 | - |
| dc.description.degree | 碩士 | - |
| dc.contributor.oralexamcommittee | 林琬琬;符文美;黃朝慶 | zh_TW |
| dc.contributor.oralexamcommittee | ;; | en |
| dc.subject.keyword | 微膠細胞,促炎性活化態,抗炎性活化態,吞噬作用,Scn1a,Nav1.1,Dravet症候群, | zh_TW |
| dc.subject.keyword | Microglia,pro-inflammation,anti-inflammation,phagocytosis,Scn1a,Nav1.1,Dravet syndrome, | en |
| dc.relation.page | 69 | - |
| dc.identifier.doi | 10.6342/NTU201803587 | - |
| dc.rights.note | 未授權 | - |
| dc.date.accepted | 2018-08-16 | - |
| dc.contributor.author-college | 醫學院 | - |
| dc.contributor.author-dept | 藥理學研究所 | - |
| 顯示於系所單位： | 藥理學科所 | |
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